The active ingredient in KALYDECO tablets is Ivacaftor, which has the following chemical name: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. Its molecular formula is C24H28N2O3 and its molecular weight is 392.49. Ivacaftor has the following structural formula:
Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL). Due to poor aqueous solubility, extensive formulation efforts were required and resulted in a spray-dried dispersion of Ivacaftor suitable for oral administration. KALYDECO containing the spray-dried dispersion of Ivacaftor is available as a light blue capsule-shaped, film-coated tablet for oral administration containing 150 mg of Ivacaftor. Each tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.
Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein.
After oral administration of a single 150 mg dose to healthy volunteers in a fed state, peak plasma concentrations (tmax) occurred at approximately 4 hours, and the mean (±SD) for AUC and Cmax were 10,600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively. After every 12-hour dosing, steady-state plasma concentrations of Ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.
The exposure of Ivacaftor increased approximately 2- to 4-fold when given with food containing fat. Therefore, KALYDECO should be administered with fat-containing food. Examples of fat-containing foods include eggs, butter, peanut butter, and cheese pizza. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.
The mean apparent volume of distribution (Vz/F) of Ivacaftor after a single dose of 275 mg of KALYDECO in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.
Ivacaftor is extensively metabolized in humans. In-vitro and clinical studies indicate that Ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of Ivacaftor in humans. M1 has approximately one-sixth the potency of Ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of Ivacaftor and is not considered pharmacologically active.
Following oral administration, the majority of Ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of Ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose. The mean apparent clearance (CL/F) of Ivacaftor was similar for healthy subjects and patients with CF. The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
The main pharmacokinetic problem associated with the oral delivery of Ivacaftor is a significant positive food effect which renders the current tablet formulation to be taken with a high fat meal which results in variability of exposure and does not allow the precise dosing of the compound.
In order to overcome the problems associated with prior conventional Ivacaftor formulations and available drug delivery systems, novel complex formulations of Ivacaftor and salts or derivatives thereof together with complexation agents and pharmaceutically acceptable excipients were prepared. The novel complexes possess instantaneous redispersibility, increased apparent solubility and permeability compared to KALYDECO, no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex in solution form.